Dosage

Adults

Seizure Disorders

Partial Seizures

After 2 weeks, may increase dosage to 200 mg daily for at least 2 weeks.13 May further increase to 300 and 400 mg daily;1239 allow ≥2 weeks between dosage changes (to achieve steady state at each dosage level).1239 Some clinicians may prefer to administer lower dosages for longer periods (in order to fully assess safety at steady state).1

Dosages >400 mg daily may not be associated with increased therapeutic benefit.1

Special Populations

Hepatic Impairment

Renal Impairment

Titrate dosage slowly.12 Do not use in patients with renal failure (GFR <50 mL/minute).1

Geriatric Patients

No specific dosage recommendations; however, select dosage cautiously, usually starting at the lower end of the dosage range, because of age-related decreases in hepatic, renal, or cardiac function and concomitant diseases and drug therapy.1

Cautions for Zonisamide

Contraindications

Known hypersensitivity to zonisamide, sulfonamides, or any ingredient in the formulation.12

Warnings/Precautions

Warnings

Hematologic Effects

Aplastic anemia and agranulocytosis reported rarely; relationship between these events and dosage or duration of therapy not established.12

Consider risk of hyperthermia when zonisamide is used concomitantly with other drugs that predispose patients to heat-related disorders.113 (See Pediatric Use under Cautions, Drugs Predisposing to Heat-related Disorders under Interactions, and Advice to Patients.)

Suicidality Risk

Increased risk of suicidality (suicidal ideation or behavior) observed in an analysis of studies using various anticonvulsants, including zonisamide, in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%).1141521 Increased suicidality risk was observed ≥1 week after initiation of anticonvulsant therapy and continued through 24 weeks.1415 Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.11415

Closely monitor all patients currently receiving or beginning anticonvulsant therapy for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression.1141521

Balance risk of suicidality with the risk of untreated illness.115 Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality.121 If suicidal thoughts or behavior emerge during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself.121 (See Advice to Patients.)

Metabolic Acidosis

Hyperchloremic, non-anion gap, metabolic acidosis reported.119 (See Pediatric Use under Cautions.) Manifestations may include hyperventilation, fatigue, anorexia, cardiac arrhythmias, or stupor.119 Generally occurs early in treatment, but may occur at any time during therapy.119

Risk appears greater at higher dosages of zonisamide, but can occur with dosages ≤25 mg daily.119 Renal disease, severe respiratory disorders, status epilepticus, diarrhea, surgery, ketogenic diets, or other drugs (e.g., acetazolamide) may predispose patients to acidosis.119 Also appears to be more frequent and severe in pediatric patients.119 (See Pediatric Use under Cautions.)

Sensitivity Reactions

Dermatologic and Sensitivity Reactions

Zonisamide is a sulfonamide; potentially fatal reactions may occur as a result of severe reactions to sulfonamides, including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias.127

Rash (usually occurring early in treatment and not dose related) reported in clinical studies.1 At least 49 cases of severe rash (Stevens-Johnson syndrome or toxic epidermal necrolysis) reported during postmarketing experience in Japan; no confirmed cases reported to date in US.1

General Precautions

Renal Calculi

In general, increasing fluid intake and urine output may reduce the risk of kidney stone formation, particularly in patients with predisposing risk factors; not known whether these measures reduce the risk of kidney stone formation in patients receiving zonisamide.1

Other Renal Effects

Substantial increases in Scr and BUN reported;1 such increases appeared to persist over time but were not progressive.1 Consider periodically monitoring renal function during zonisamide therapy.1

Discontinue use in patients who develop acute renal failure or clinically important, sustained increases in Scr and BUN.1

Status Epilepticus

In controlled studies, status epilepticus occurred in 1.1 or 0% of patients receiving zonisamide or placebo, respectively.1 In all (uncontrolled and controlled) clinical studies, the incidence of status epilepticus in patients receiving zonisamide was 1%.1

Specific Populations

Pregnancy

North American Antiepileptic Drug (NAAED) Pregnancy Registry (for patients) at 888-233-2334 or [Web].1

If zonisamide-induced metabolic acidosis occurs during pregnancy, may affect fetal development (i.e., decreased fetal growth, decreased fetal oxygenation, fetal death) and the ability of the fetus to tolerate labor.119 In pregnant women, monitor and treat metabolic acidosis in the same manner as nonpregnant patients.1 In addition, monitor neonates for metabolic acidosis because of possible fetal drug transfer and transient metabolic acidosis following birth.1

Lactation

Pediatric Use

Safety and efficacy not established in children <16 years of age.119 However, the drug has been used in some pediatric patients† for the treatment of epilepsy.19222324252627

Studies conducted with pediatric patients indicate that frequency of some adverse effects (e.g., metabolic acidosis, oligohidrosis and hyperthermia) may be increased compared with adults.1

Oligohidrosis and hyperthermia reported in pediatric patients (1.6–17 years of age) and sometimes have resulted in heat stroke and hospitalization.1231113 (See Oligohidrosis and Hyperthermia under Cautions.)

If used in pediatric patients (not an FDA-labeled population), closely monitor for evidence of decreased sweating and increased body temperature, especially in warm or hot weather or when other drugs that predispose patients to heat-related disorders (e.g., carbonic anhydrase inhibitors) are used concomitantly.11326 (See Drugs Predisposing to Heat-related Disorders under Interactions.)

Pediatric patients may be at increased risk for zonisamide-induced metabolic acidosis; may be more severe in younger patients.19 Specific effects of zonisamide on growth and bone not studied; chronic metabolic acidosis may reduce growth rates in pediatric patients, resulting in a reduction in the maximal height achieved.19 (See Metabolic Acidosis under Cautions, Specific Drugs under Interactions, and Advice to Patients.)

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.1

Hepatic Impairment

Use with caution in patients with hepatic impairment; slower dosage titration and more frequent monitoring may be necessary.1

Renal Impairment

Use with caution in patients with renal impairment; slower dosage titration and more frequent monitoring may be necessary.1

Because of insufficient experience concerning dosage and toxicity, do not use in patients with renal failure (GFR <50 mL/minute).1

Interactions for Zonisamide

Drugs Metabolized by or Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Pharmacokinetics of zonisamide may be altered, but not expected to be clinically important; dosage adjustment not necessary.12

CYP3A4 inducers: Zonisamide concentrations may be altered when CYP3A4-inducing drugs are introduced or withdrawn from therapy, or dosage is adjusted.1 Closely monitor patients and adjust dosage of zonisamide as necessary.1

Specific Drugs

Clinically important changes in plasma zonisamide concentrations may occur when carbamazepine is introduced or withdrawn, or dosage adjusted;123 no change in steady-state plasma carbamazepine concentrations128

Closely monitor patient; dosage adjustment of zonisamide may be required12

Oral contraceptive containing ethinyl estradiol and norethisterone: No changes in concentrations of either contraceptive component128

Phenobarbital

Clinically important changes in plasma zonisamide concentrations may occur when phenobarbital is introduced or withdrawn, or dosage adjusted1

Closely monitor patient; dosage adjustment of zonisamide may be required1

Phenytoin

Clinically important changes in plasma zonisamide concentrations may occur when phenytoin is introduced or withdrawn, or dosage adjusted;123 no change in steady-state plasma phenytoin concentrations128

Closely monitor patient; dosage adjustment of zonisamide may be required1

Plasma Protein Binding

Elimination

Metabolism

Undergoes acetylation to form N-acetyl zonisamide, subsequent reduction to form 2-sulfamoylacetyl phenol, and further glucuronide conjugation.13 The reduction of N-acetyl zonisamide is mediated by CYP3A4.123

Advice to Patients

Risk of serious skin rash that can cause death; these skin reactions are more likely to happen within the first 4 months of starting therapy, but may occur later.1 Importance of immediately contacting clinician if skin rash occurs.1

Importance of patients being aware that zonisamide can prevent sweating, which makes it harder for the body to cool down when it gets very hot; this is more likely to occur in warmer weather, in children, and during physical exercise.11326 Importance of avoiding exposure to heat, maintaining adequate hydration, and informing clinicians immediately if fever or increased body temperature and/or decreased sweating occurs, particularly in children or in hot weather.11326

Risk of blood cell abnormalities such as reduced RBC and WBC counts.1 Importance of contacting clinician if fever, sore throat, sores in the mouth, or unusual bruising occurs.1

Risk of suicidality (anticonvulsants, including zonisamide, may increase risk of suicidal thoughts or actions in about 1 in 500 people).11521 Importance of patients, family, and caregivers being alert to day-to-day changes in mood, behavior, and actions and immediately informing clinician of any new or worrisome behaviors (e.g., talking or thinking about wanting to hurt oneself or end one’s life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions).115

Importance of advising patients that zonisamide may cause metabolic acidosis and that blood tests to measure serum bicarbonate concentrations may be performed.119 Patients should contact their clinician immediately if they develop symptoms of metabolic acidosis such as fast breathing (hyperventilation), fatigue, loss of appetite, irregular heart beat, palpitations, or unconsciousness.119

Potential for drowsiness, especially at higher dosages.1 Importance of advising patients to avoid driving or operating complex machinery until experience with the drug’s effects has been established.1 Because of the potential for additive CNS effects, patients should be advised to use caution when consuming alcohol or taking concomitant CNS depressants.1

Risk of kidney stones.1 Importance of informing patients that increasing fluid intake (i.e., by drinking 6–8 glasses of water a day) and urine output may reduce the risk of stone formation, particularly in those with predisposing factors.1 Importance of immediately reporting symptoms of kidney stones (e.g., sudden back pain, abdominal pain, and/or blood in urine) to clinician.1

Importance of women informing clinicians if they are or plan to become pregnant.119 Importance of informing women who are or plan to become pregnant that zonisamide may cause metabolic acidosis, which may negatively affect fetal development during pregnancy.19 Importance of clinicians informing women about the existence of and encouraging enrollment in pregnancy registries (see Pregnancy under Cautions).1

Importance of informing nursing women and those who plan to breast-feed that zonisamide can appear in the breast milk, and that the effects of this exposure on the infant are unknown.19 Importance of women informing clinicians if they plan to breast-feed.119

Importance of swallowing zonisamide capsules whole and not biting into or breaking into the capsules; zonisamide may be taken with or without food.1

Importance of informing patients not to stop taking zonisamide without talking to their clinician since stopping the drug suddenly can cause serious problems, including seizures.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription drugs, OTC drugs, and special diets (e.g., ketogenic diet), as well as any concomitant illnesses (e.g., liver disease, kidney disease, severe lung disorders, diarrhea, surgery, depression, bipolar disorder) or family history of suicidality or bipolar disorder.11319

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.